Tag: CNS: Central Nervous System

An Overview of Neuroepigenetics

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Introduction

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

Mechanisms

Neuroepigenetic mechanisms regulate gene expression in the neuron. Often, these changes take place due to recurring stimuli. Neuroepigenetic mechanisms involve proteins or protein pathways that regulate gene expression by adding, editing or reading epigenetic marks such as methylation or acetylation. Some of these mechanisms include ATP-dependent chromatin remodelling, LINE1, and prion protein-based modifications. Other silencing mechanisms include the recruitment of specialised proteins that methylate DNA such that the core promoter element is inaccessible to transcription factors and RNA polymerase. As a result, transcription is no longer possible. One such protein pathway is the REST co-repressor complex pathway. There are also several non-coding RNAs that regulate neural function at the epigenetic level. These mechanisms, along with neural histone methylation, affect arrangement of synapses, neuroplasticity, and play a key role in learning and memory.

Methylation

DNA methyltransferases (DNMTs) are involved in regulation of the electrophysiological landscape of the brain through methylation of CpGs. Several studies have shown that inhibition or depletion of DNMT1 activity during neural maturation leads to hypomethylation of the neurons by removing the cell’s ability to maintain methylation marks in the chromatin. This gradual loss of methylation marks leads to changes in the expression of crucial developmental genes that may be dosage sensitive, leading to neural degeneration. This was observed in the mature neurons in the dorsal portion of the mouse prosencephalon, where there was significantly greater amounts of neural degeneration and poor neural signalling in the absence of DNMT1. Despite poor survival rates amongst the DNMT1-depleted neurons, some of the cells persisted throughout the lifespan of the organism. The surviving cells reaffirmed that the loss of DNMT1 led to hypomethylation in the neural cell genome. These cells also exhibited poor neural functioning. In fact, a global loss of neural functioning was also observed in these model organisms, with the greatest amounts neural degeneration occurring in the prosencephalon.

Other studies showed a trend for DNMT3a and DNMT3b. However, these DNMT’s add new methyl marks on unmethylated DNA, unlike DNMT1. Like DNMT1, the loss of DNMT3a and 3b resulted in neuromuscular degeneration two months after birth, as well as poor survival rates amongst the progeny of the mutant cells, even though DNMT3a does not regularly function to maintain methylation marks. This conundrum was addressed by other studies which recorded rare loci in mature neurons where DNMT3a acted as a maintenance DNMT. The Gfap locus, which codes for the formation and regulation of the cytoskeleton of astrocytes, is one such locus where this activity is observed. The gene is regularly methylated to downregulate glioma related cancers. DNMT inhibition leads to decreased methylation and increased synaptic activity. Several studies show that the methylation-related increase or decrease in synaptic activity occurs due to the upregulation or downregulation of receptors at the neurological synapse. Such receptor regulation plays a major role in many important mechanisms, such as the ‘fight or flight’ response. The glucocorticoid receptor (GR) is the most studied of these receptors. During stressful circumstances, there is a signalling cascade that begins from the pituitary gland and terminates due to a negative feedback loop from the adrenal gland. In this loop, the increase in the levels of the stress response hormone results in the increase of GR. Increase in GR results in the decrease of cellular response to the hormone levels. It has been shown that methylation of the I7 exon within the GR locus leads to a lower level of basal GR expression in mice. These mice were more susceptible to high levels of stress as opposed to mice with lower levels of methylation at the I7 exon. Up-regulation or down-regulation of receptors through methylation leads to change in synaptic activity of the neuron.

Hypermethylation, CpG Islands, and Tumour Suppressing Genes

CpG Islands (CGIs) are regulatory elements that can influence gene expression by allowing or interfering with transcription initiation or enhancer activity. CGIs are generally interspersed with the promoter regions of the genes they affect and may also affect more than one promoter region. In addition they may also include enhancer elements and be separate from the transcription start site. Hypermethylation at key CGIs can effectively silence expression of tumour suppressing genes and is common in gliomas. Tumour suppressing genes are those which inhibit a cell’s progression towards cancer. These genes are commonly associated with important functions which regulate cell-cycle events. For example, PI3K and p53 pathways are affected by CGI promoter hypermethylation, this includes the promoters of the genes CDKN2/p16, RB, PTEN, TP53 and p14ARF. Importantly, glioblastomas are known to have high frequency of methylation at CGIs/promoter sites. For example, Epithelial Membrane Protein 3 (EMP3) is a gene which is involved in cell proliferation as well as cellular interactions. It is also thought to function as a tumour suppressor, and in glioblastomas is shown to be silenced via hypermethylation. Furthermore, introduction of the gene into EMP3-silenced neuroblasts results in reduced colony formation as well as suppressed tumour growth. In contrast, hypermethylation of promoter sites can also inhibit activity of oncogenes and prevent tumorigenesis. Such oncogenic pathways as the transformation growth factor (TGF)-beta signalling pathway stimulate cells to proliferate. In glioblastomas the overactivity of this pathway is associated with aggressive forms of tumour growth. Hypermethylation of PDGF-B, the TGF-beta target, inhibits uncontrolled proliferation.

Hypomethylation and Aberrant Histone Modification

Global reduction in methylation is implicated in tumorigenesis. More specifically, wide spread CpG demethylation, contributing to global hypomethylation, is known to cause genomic instability leading to development of tumours. An important effect of this DNA modification is its transcriptional activation of oncogenes. For example, expression of MAGEA1 enhanced by hypomethylation interferes with p53 function.

Aberrant patterns of histone modifications can also take place at specific loci and ultimately manipulate gene activity. In terms of CGI promoter sites, methylation and loss of acetylation occurs frequently at H3K9. Furthermore, H3K9 dimethylation and trimethylation are repressive marks which, along with bivalent differentially methylated domains, are hypothesized to make tumour suppressing genes more susceptible to silencing. Abnormal presence or lack of methylation in glioblastomas are strongly linked to genes which regulate apoptosis, DNA repair, cell proliferation, and tumour suppression. One of the best known examples of genes affected by aberrant methylation that contributes to formation of glioblastomas is MGMT, a gene involved in DNA repair which encodes the protein O6-methylguanine-DNA methyltransferase. Methylation of the MGMT promoter is an important predictor of the effectiveness of alkylating agents to target glioblastomas. Hypermethylation of the MGMT promoter causes transcriptional silencing and is found in several cancer types including glioma, lymphoma, breast cancer, prostate cancer, and retinoblastoma.

Neuroplasticity

Neuroplasticity refers to the ability of the brain to undergo synaptic rearrangement as a response to recurring stimuli. Neurotrophin proteins play a major role in synaptic rearrangement, amongst other factors. Depletion of neurotrophin BDNF or BDNF signalling is one of the main factors in developing diseases such as Alzheimer’s disease, Huntington’s disease, and depression. Neuroplasticity can also occur as a consequence of targeted epigenetic modifications such as methylation and acetylation. Exposure to certain recurring stimuli leads to demethylation of particular loci and remethylation in a pattern that leads to a response to that particular stimulus. Like the histone readers, erasers and writers also modify histones by removing and adding modifying marks respectively. An eraser, neuroLSD1, is a modified version of the original Lysine Demethylase 1(LSD1) that exists only in neurons and assists with neuronal maturation. Although both versions of LSD1 share the same target, their expression patterns are vastly different and neuroLSD1 is a truncated version of LSD1. NeuroLSD1 increases the expression of immediate early genes (IEGs) involved in cell maturation. Recurring stimuli lead to differential expression of neuroLSD1, leading to rearrangement of loci. The eraser is also thought to play a major role in the learning of many complex behaviors and is way through which genes interact with the environment.

Neurodegenerative Diseases

Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease known to progressively affect memory and incite cognitive degradation. Epigenetic modifications both globally and on specific candidate genes are thought to contribute to the aetiology of this disease. Immunohistochemical analysis of post-mortem brain tissues across several studies have revealed global decreases in both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in AD patients compared with controls. However, conflicting evidence has shown elevated levels of these epigenetic markers in the same tissues. Furthermore, these modifications appear to be affected early on in tissues associated with the pathophysiology of AD. The presence of 5mC at the promoters of genes is generally associated with gene silencing. 5hmC, which is the oxidised product of 5mC, via ten-eleven-translocase (TET), is thought to be associated with activation of gene expression, though the mechanisms underlying this activation are not fully understood.

Regardless of variations in results of methylomic analysis across studies, it is known that the presence of 5hmC increases with differentiation and aging of cells in the brain. Furthermore, genes which have a high prevalence of 5hmC are also implicated in the pathology of other age related neurodegenerative diseases, and are key regulators of ion transport, neuronal development, and cell death. For example, over-expression of 5-Lipoxygenase (5-LOX), an enzyme which generates pro-inflammatory mediators from arachidonic acid, in AD brains is associated with high prevalence of 5hmC at the 5-LOX gene promoter region.

Amyotrophic Lateral Sclerosis

DNA modifications at different transcriptional sites have been shown to contribute to neurodegenerative diseases. These include harmful transcriptional alterations such as those found in motor neuron functionality associated with Amyotrophic Lateral Sclerosis (ALS). Degeneration of upper and lower motor neurons, which contributes to muscle atrophy in ALS patients, is linked to chromatin modifications among a group of key genes. One important site that is regulated by epigenetic events is the hexanucleotide repeat expansion in C9orf72 within the chromosome 9p21. Hypermethylation of the C9orf72 related CpG Islands is shown to be associated with repeat expansion in ALS affected tissues. Overall, silencing of the C9orf72 gene may result in haploinsufficiency, and may therefore influence the presentation of disease. The activity of chromatin modifiers is also linked to prevalence of ALS. DNMT3A is an important methylating agent and has been shown to be present throughout the central nervous systems of those with ALS. Furthermore, over-expression of this de novo methyl transferase is also implicated in cell death of motor-neuron analogues.

Mutations in the FUS gene, that encodes an RNA/DNA binding protein, are causally linked to ALS. ALS patients with such mutations have increased levels of DNA damage. The protein encoded by the FUS gene is employed in the DNA damage response. It is recruited to DNA double-strand breaks and catalyses recombinational repair of such breaks. In response to DNA damage, the FUS protein also interacts with histone deacetylase I, a protein employed in epigenetic alteration of histones. This interaction is necessary for efficient DNA repair. These findings suggest that defects in epigenetic signalling and DNA repair contribute to the pathogenesis of ALS.

Neuro-oncology

A multitude of genetic and epigenetic changes in DNA profiles in brain cells are thought to be linked to tumourgenesis. These alterations, along with changes in protein functions, are shown to induce uncontrolled cell proliferation, expansion, and metastasis. While genetic events such as deletions, translocations, and amplification give rise to activation of oncogenes and deactivation of tumour suppressing genes, epigenetic changes silence or up-regulate these same genes through key chromatin modifications.

Neurotoxicity

Neurotoxicity refers to damage made to the central or peripheral nervous systems due to chemical, biological, or physical exposure to toxins. Neurotoxicity can occur at any age and its effects may be short-term or long-term, depending on the mechanism of action of the neurotoxin and degree of exposure.

Certain metals are considered essential due to their role in key biochemical and physiological pathways, while the remaining metals are characterized as being nonessential. Nonessential metals do not serve a purpose in any biological pathway and the presence and accumulation in the brain of most can lead to neurotoxicity. These nonessential metals, when found inside the body compete with essential metals for binding sites, upset antioxidant balance, and their accumulation in the brain can lead to harmful side effects, such as depression and intellectual disability. An increase in nonessential heavy metal concentrations in air, water and food sources, and household products has increased the risk of chronic exposure.

Acetylation, methylation and histone modification are some of the most common epigenetic markers. While these changes do not directly affect the DNA sequence, they are able to alter the accessibility to genetic components, such as the promoter or enhancer regions, necessary for gene expression. Studies have shown that long-term maternal exposure to lead (Pb) contributes to decreased methylation in areas of the foetal epigenome, for example the interspaced repetitive sequences (IRSs) Alu1 and LINE-1. The hypomethylation of these IRSs has been linked to increased risk for cancers and autoimmune diseases later in life. Additionally, studies have found a relationship between chronic prenatal Pb exposure and neurological diseases, such as Alzheimer’s and schizophrenia, as well as developmental issues. Furthermore, the acetylation and methylation changes induced by overexposure to lead result in decreased neurogenesis and neuron differentiation ability, and consequently interfere with early brain development.

Overexposure to essential metals can also have detrimental consequences on the epigenome. For example, when manganese, a metal normally used by the body as a cofactor, is present at high concentrations in the blood it can negatively affect the central nervous system. Studies have shown that accumulation of manganese leads to dopaminergic cell death and consequently plays a role in the onset of Parkinson’s disease (PD). A hallmark of Parkinson’s disease is the accumulation of α-Synuclein in the brain. Increased exposure to manganese leads to the downregulation of protein kinase C delta (PKCδ) through decreased acetylation and results in the misfolding of the α-Synuclein protein that allows aggregation and triggers apoptosis of dopaminergic cells.

Research

The field has only recently seen a growth in interest, as well as in research, due to technological advancements that facilitate better resolution of the minute modifications made to DNA. However, even with the significant advances in technology, studying the biology of neurological phenomena, such as cognition and addiction, comes with its own set of challenges. Biological study of cognitive processes, especially with humans, has many ethical caveats. Some procedures, such as brain biopsies of Rett Syndrome patients, usually call for a fresh tissue sample that can only be extricated from the brain of deceased individual. In such cases, the researchers have no control over the age of brain tissue sample, thereby limiting research options. In case of addiction to substances such as alcohol, researchers utilise mouse models to mirror the human version of the disease (even though mouse models do not translate very well to human models). However, the mouse models are administered greater volumes of ethanol than humans normally consume in order to obtain more prominent phenotypes. Therefore, while the model organism and the tissue samples provide an accurate approximation of the biology of neurological phenomena, these approaches do not provide a complete and precise picture of the exact processes underlying a phenotype or a disease.

Neuroepigenetics had also remained underdeveloped due to the controversy surrounding the classification of genetic modifications in matured neurons as epigenetic phenomena. This discussion arises due to the fact that neurons do not undergo mitosis after maturation, yet the conventional definition of epigenetic phenomena emphasizes heritable changes passed on from parent to offspring. However, various histone modifications are placed by epigenetic modifiers such as DNA methyltransferases (DNMT) in neurons and these marks regulate gene expression throughout the life span of the neuron. The modifications heavily influence gene expression and arrangement of synapses within the brain. Finally, although not inherited, most of these marks are maintained throughout the life of the cell once they are placed on chromatin.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Neuroepigenetics >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Dexmethylphenide?

Published on by Andrew MarshallLeave a comment

Introduction

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. It is taken by mouth. The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate.

Common side effects include abdominal pain, loss of appetite, and fever. Serious side effects may include abuse, psychosis, sudden cardiac death, mania, anaphylaxis, seizures, and dangerously prolonged erection. Safety during pregnancy and breastfeeding is unclear. Dexmethylphenidate is a central nervous system (CNS) stimulant. How it works in ADHD is unclear.

Dexmethylphenidate was approved for medical use in the United States in 2001. It is available as a generic medication. In 2020, it was the 130th most commonly prescribed medication in the United States, with more than 4 million prescriptions.

Medical Uses

Dexmethylphenidate is used as a treatment for ADHD, usually along with psychological, educational, behavioural or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behaviour. Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo. It also showed greater efficacy than osmotic controlled-release oral delivery system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.

Contraindications

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine, and tranylcypromine), or individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks. Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on foetal development. In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it “is not a major human teratogen”.

Adverse Effects

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), Oromandibular dystonia, lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure, and heart rate (typically mild), and tachycardia (rapid heart rate). Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.

Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day.

There is some evidence of mild reductions in height with prolonged treatment in children. This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.

Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.

Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms. It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania. There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link. Logorrhea is occasionally reported and visual hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.

US Food and Drug Administration-commissioned studies in 2011 indicate that in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death. The certainty of the evidence was stated as very low.

The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children.

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, agitation, tremors, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache, tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse. A methylphenidate overdose is rarely fatal with appropriate care. Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychotics, α-adrenoceptor agonists and propofol serving as second-line therapies.

Addiction and Dependence

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs; accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug. When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.

Biomolecular Mechanisms

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e. dopamine reuptake inhibition) in the brain’s reward system. At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system; consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction.

Interactions

Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations. There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification, not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.

Mode of Activity

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET), which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system. Moreover, it is thought to “increase the release of these monoamines into the extraneuronal space.”

Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio between the SS and RR enantiomers of MPH. Dexmethylphenidate (d-threo-methylphenidate) is a preparation of the RR enantiomer of methylphenidate. In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product

Pharmacology

Dexmethylphenidate has a 4–6 hour duration of effect. A long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability. It has also been demonstrated to reduce ADHD symptoms in both children and adults. d-MPH has a similar side-effect profile to MPH and can be administered without regard to food intake.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Dexmethylphenidate >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is the Gut-Brain Axis?

Published on by Andrew Marshall1 Comment

Introduction

The gut-brain axis is the biochemical signalling that takes place between the gastrointestinal tract (GI tract) and the central nervous system (CNS).

The term “gut-brain axis” is occasionally used to refer to the role of the gut flora in the interplay as well, whereas the term “microbiota–gut–brain (MGB or BGM) axis” explicitly includes the role of gut flora in the biochemical signalling events that take place between the GI tract and CNS.

Broadly defined, the gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems, including the hypothalamic-pituitary-adrenal axis (HPA axis), sympathetic and parasympathetic arms of the autonomic nervous system, including the enteric nervous system and the vagus nerve, and the gut microbiota. The first of the brain-gut interactions shown, was the cephalic phase of digestion, in the release of gastric and pancreatic secretions in response to sensory signals, such as the smell and sight of food. This was first demonstrated by Pavlov.

Interest in the field was sparked by a 2004 study showing that germ-free (GF) mice showed an exaggerated HPA axis response to stress compared to non-GF laboratory mice.

As of October 2016, most of the work done on the role of gut flora in the gut-brain axis had been conducted in animals, or on characterising the various neuroactive compounds that gut flora can produce. Studies with humans – measuring variations in gut flora between people with various psychiatric and neurological conditions or when stressed, or measuring effects of various probiotics (dubbed “psychobiotics” in this context) – had generally been small and were just beginning to be generalised. Whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut–brain axis, remained unclear.

Gut Flora

The gut flora is the complex community of microorganisms that live in the digestive tracts of humans and other animals. The gut metagenome is the aggregate of all the genomes of gut microbiota. The gut is one niche that human microbiota inhabit.

In humans, the gut microbiota has the largest quantity of bacteria and the greatest number of species, compared to other areas of the body. In humans, the gut flora is established at one to two years after birth; by that time, the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to pathogenic organisms.

The relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship. Human gut microorganisms benefit the host by collecting the energy from the fermentation of undigested carbohydrates and the subsequent absorption of short-chain fatty acids (SCFAs), acetate, butyrate, and propionate. Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolising bile acids, sterols, and xenobiotics. The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ; dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.

The composition of human gut flora changes over time, when the diet changes, and as overall health changes.

Enteric Nervous System

The enteric nervous system is one of the main divisions of the nervous system and consists of a mesh-like system of neurons that governs the function of the gastrointestinal system; it has been described as a “second brain” for several reasons. The enteric nervous system can operate autonomously. It normally communicates with the central nervous system (CNS) through the parasympathetic (e.g. via the vagus nerve) and sympathetic (e.g. via the prevertebral ganglia) nervous systems. However, vertebrate studies show that when the vagus nerve is severed, the enteric nervous system continues to function.

In vertebrates, the enteric nervous system includes efferent neurons, afferent neurons, and interneurons, all of which make the enteric nervous system capable of carrying reflexes in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. Through intestinal muscles, the motor neurons control peristalsis and churning of intestinal contents. Other neurons control the secretion of enzymes. The enteric nervous system also makes use of more than 30 neurotransmitters, most of which are identical to the ones found in CNS, such as acetylcholine, dopamine, and serotonin. More than 90% of the body’s serotonin lies in the gut, as well as about 50% of the body’s dopamine; the dual function of these neurotransmitters is an active part of gut-brain research.

The first of the gut-brain interactions was shown to be between the sight and smell of food and the release of gastric secretions, known as the cephalic phase, or cephalic response of digestion.

Gut-Brain Integration

The gut-brain axis, a bidirectional neurohumoral communication system, is important for maintaining homeostasis and is regulated through the central and enteric nervous systems and the neural, endocrine, immune, and metabolic pathways, and especially including the hypothalamic-pituitary-adrenal axis (HPA axis). That term has been expanded to include the role of the gut flora as part of the “microbiome-gut-brain axis”, a linkage of functions including the gut flora.

Interest in the field was sparked by a 2004 study (Nobuyuki Sudo and Yoichi Chida) showing that germ-free mice (genetically homogeneous laboratory mice, birthed and raised in an antiseptic environment) showed an exaggerated HPA axis response to stress, compared to non-GF laboratory mice.

The gut flora can produce a range of neuroactive molecules, such as acetylcholine, catecholamines, γ-aminobutyric acid, histamine, melatonin, and serotonin, which are essential for regulating peristalsis and sensation in the gut. Changes in the composition of the gut flora due to diet, drugs, or disease correlate with changes in levels of circulating cytokines, some of which can affect brain function. The gut flora also release molecules that can directly activate the vagus nerve, which transmits information about the state of the intestines to the brain.

Likewise, chronic or acutely stressful situations activate the hypothalamic-pituitary-adrenal axis, causing changes in the gut flora and intestinal epithelium, and possibly having systemic effects. Additionally, the cholinergic anti-inflammatory pathway, signalling through the vagus nerve, affects the gut epithelium and flora. Hunger and satiety are integrated in the brain, and the presence or absence of food in the gut and types of food present also affect the composition and activity of gut flora.

That said, most of the work that has been done on the role of gut flora in the gut-brain axis has been conducted in animals, including the highly artificial germ-free mice. As of 2016, studies with humans measuring changes to gut flora in response to stress, or measuring effects of various probiotics, have generally been small and cannot be generalised; whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut-brain axis, remains unclear.

The history of ideas about a relationship between the gut and the mind dates from the nineteenth century. The concepts of dyspepsia and neurasthenia gastrica referred to the influence of the gut on human emotions and thoughts.

Gut-Brain-Skin Axis

A unifying theory that tied gastrointestinal mechanisms to anxiety, depression, and skin conditions such as acne was proposed as early as 1930. In a paper in 1930, it was proposed that emotional states might alter normal intestinal flora which could lead to increased intestinal permeability and therefore contribute to systemic inflammation. Many aspects of this theory have been validated since then. Gut microbiota and oral probiotics have been found to influence systemic inflammation, oxidative stress, glycaemic control, tissue lipid content, and mood.

Research

Probiotics

A 2016 systematic review of laboratory animal studies and preliminary human clinical trials using commercially available strains of probiotic bacteria found that certain species of the Bifidobacterium and Lactobacillus genera (i.e. B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei) had the most potential to be useful for certain central nervous system disorders.

Anxiety and Mood Disorders

As of 2018 work on the relationship between gut flora and anxiety disorders and mood disorders, as well as attempts to influence that relationship using probiotics or prebiotics (called “psychobiotics”), was at an early stage, with insufficient evidence to draw conclusions about a causal role for gut flora changes in these conditions, or about the efficacy of any probiotic or prebiotic treatment.

People with anxiety and mood disorders tend to have gastrointestinal problems; small studies have been conducted to compare the gut flora of people with major depressive disorder and healthy people, but those studies have had contradictory results.

Much interest was generated in the potential role of gut flora in anxiety disorders, and more generally in the role of gut flora in the gut-brain axis, by studies published in 2004 showing that germ-free mice have an exaggerated HPA axis response to stress caused by being restrained, which was reversed by colonising their gut with a Bifidobacterium species. Studies looking at maternal separation for rats shows neonatal stress leads to long-term changes in the gut microbiota such as its diversity and composition, which also led to stress and anxiety-like behaviour. Additionally, while much work had been done as of 2016 to characterise various neurotransmitters known to be involved in anxiety and mood disorders that gut flora can produce (for example, Escherichia, Bacillus, and Saccharomyces species can produce noradrenalin; Candida, Streptococcus, and Escherichia species can produce serotonin, etc.) the interrelationships and pathways by which the gut flora might affect anxiety in humans were unclear.

In one study, germ-free mice underwent faecal transplants with microbes from humans with or without major depressive disorder (MDD). Mice with microbes from humans with MDD displayed more behaviours associated with anxiety and depression than mice transplanted with microbes from humans without MDD. The taxonomic composition of microbiota between depressed patients and healthy patients, as well as between the respective mice, also differed. Germ-free mice in another study also displayed behaviours associated with anxiety and depression as compared to mice with normal microbiota, and had higher levels of corticosterone after exposure to behavioural tests. Using rodents in microbiome and mental health studies allows researchers to compare behaviour and microbial composition of rodents to humans, ideally to elucidate therapeutic application for mental disorders.

Additionally, there is a link between the gut microbiome, mood disorders and anxiety, and sleep. The microbial composition of the gut microbiome changes depending on the time of day, meaning that throughout the day, the gut is exposed to varying metabolites produced by the microbes active during that time. These time-dependent microbial changes are associated with differences in the transcription of circadian clock genes involved in circadian rhythm. One mouse study showed that altering clock gene transcription by disrupting circadian rhythm, such as through sleep deprivation, potentially has a direct effect on the composition of the gut microbiome. Another study found that mice that could not produce the CLOCK protein, made by a clock gene, were more likely to develop depression. Stress and sleep disturbances can lead to greater gut mucosal permeability via activation of the HPA axis. This in turn causes immune inflammatory responses that contribute to the development of illnesses that cause depression and anxiety.

Autism

Around 70% of people with autism also have gastrointestinal problems, and autism is often diagnosed at the time that the gut flora becomes established, indicating that there may be a connection between autism and gut flora. Some studies have found differences in the gut flora of children with autism compared with children without autism – most notably elevations in the amount of Clostridium in the stools of children with autism compared with the stools of the children without – but these results have not been consistently replicated. Many of the environmental factors thought to be relevant to the development of autism would also affect the gut flora, leaving open the question of whether specific developments in the gut flora drive the development of autism or whether those developments happen concurrently. As of 2016, studies with probiotics had only been conducted with animals; studies of other dietary changes to treat autism have been inconclusive.

Parkinson’s Disease

As of 2015, one study had been conducted comparing the gut flora of people with Parkinson’s disease to healthy controls; in that study people with Parkinson’s had lower levels of Prevotellaceae and people with Parkinson’s who had higher levels of Enterobacteriaceae had more clinically severe symptoms; the authors of the study drew no conclusions about whether gut flora changes were driving the disease or vice versa.

CNS Endothelium: Respiratory & Affective Disorders associated with Vascular Diseases

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Research Paper Title

Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice.

Background

Carbon dioxide (CO2), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity.

Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear.

Here, the researchers found that GPR4, an endothelial H+ receptor, and endothelial Gαq/11 proteins mediate the CO2/H+ effect on cerebrovascular reactivity in mice. CO2/H+ leads to constriction of vessels in the brainstem area that controls respiration.

The consequential washout of CO2, if cerebrovascular reactivity is impaired, reduces respiration.

In contrast, CO2 dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO2 effect on anxiety.

Even at atmospheric CO2 concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function.

The site-specific reactivity of vessels to CO2 is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells.

This data suggests the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.

Reference

Wenzel, J., Hansen, C.E., Bettoni, C., Vogt, M.A., Lembrich, B., Natsagdorj, R., Huber, G., Brands, J., Schmidt, K., Assmann, J.C., Stölting, I., Saar, K., Sedlacik, J., Fiehler, J., Ludewig, P., Wegmann, M., Feller, N., Richter, M., Müller-Fielitz, H., Walther, T., König, G.M., Kostenis, E., Raasch, W., Hübner, N., Gass, P., Offermanns, S., de Wit, C., Wagner, C.A. & Schwaninger, M. (2020) Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice. Proceedings of the National Academy of Sciences of the United States of America. 117(3), pp.1753-1761. doi: 10.1073/pnas.1907467117. Epub 2020 Jan 2.